Obesity is a risk factor for several preventable diseases. In recent years, there has been a dramatic rise in the consumer use of dietary supplements for weight management. Raspberry ketone [4-(p-hydroxyphenyl)-2-butanone] is derived from the fruit of the red raspberry (Rubus idaeus) and has purported antiobesity properties. Despite the supplement's consumer popularity, raspberry ketone has not been systematically tested to determine effectiveness for weight loss. The overall objective of this project is to determine the mechanisms by which raspberry ketone decreases feeding and prevents the metabolic consequences of diet-induced obesity. The central hypothesis of this project that raspberry ketone has a dual action to suppress feeding by activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) channels and to increase fat oxidation mediated by peroxisome proliferator- activated receptor (PPAR) alpha pathways. This proposal will use diet-induced obese (DIO) mice to investigate the acute and long-term effects of raspberry ketone on body weight homeostasis and metabolic signatures. Aim 1 will determine the mechanism(s) by which raspberry ketone suppresses feeding. This will include caloric intake and meal patterns, gene expression of gastrointestinal and hypothalamic feeding-related signals, circulating hormones, and potential for hepatic and intestinal pathology. Aim 2 will determine the mechanism(s) by which raspberry ketone influences metabolic outcomes. This will include measuring energy expenditure, thermoregulatory activity, hemodynamic parameters, and glucose homeostasis. Aim 3 will determine the bioacessibility of raspberry ketone using a functional model of the human digestive system (TNO intestinal model) and in vivo animal model to determine the metabolism and bioavailability of raspberry ketone. The findings from these studies will identify the in vivo mechanisms of preventative actions of raspberry ketone on weight gain and other obesity-related outcomes. The proposed project is relevant to the overall NIH goal of enhancing translational research by providing critical mechanistic data on a commonly used dietary supplement.